The 3,5-isoxazolidinediones and 2-isoxazolin-5-ones demonstrated potent cytotoxicity against the growth of human Tmolt3 T cell leukemia, murine P388 and L1210 leukemias, as well as human HeLa-S3 uterine carcinoma and glioma tumor cell growth. The specificity of the 3,5-isoxazolidinedione and 2-isoxazoline-5one derivatives as cytotoxic agents varied with the histological type of tumor cell. Selected compounds were active against solid HeLa uterine, KB nasopharynx, skin A43 1, SW-480 adenocarcinoma, osteosarcoma and glioma growth. Selected compounds demonstrated in vivo antineoplastic activity against Ehrlich ascites carcinoma growth. In L-1210 leukemia cells, the agents blocked DNA and protein synthesis at 25,50 and 100 pM over 60 min. The agents were effective in reducing rate limiting enzymes in the de now purine and pyrimidine pathways. In addition they suppressed dihydrofolate reductase and ribonucleoside reductase activities with moderate inhibition of DNA and RNA polymerase activities. DNA itself was not a target of the agents. similarity in structure to pyrazolidinediones wherein an oxygen has replaced one of the nitrogen atoms in the five-membered pyrazolidine ring.
Synthesis
The derivatives that were synthesized are shown in Table .
The N-phenyl derivative 3 was prepared by the reaction of N-phenylhydroxylamine and diethylmalonyl chloride in the presence of triethylamine. Compounds 4-16 were formed by heating in refluxing 1 ,Zdimethoxyethane a 50% excess of the appropriate halo ketones, esters, amides and nitriles with Table 1. Structures and in vivo antineoplastic activity of 3.5-isoxazolidinedione [I] and 2-isoxazoline-5-one [11] derivatives at 8 mg/kg/day, i.p. in the Ehrlich ascites carcinoma screen [N = 61.